DESCRIPTION: In this renewal proposal, the principal investigator notes that The development of new methods for the regiospecific synthesis of highly substituted aromatic compounds is an important goal in organic and medicinal chemistry and that many compounds of pharmaceutical importance fall within this realm, and that the needs for analog syntheses and structure-activity relationship studies further highlight the significance of providing versatile new routes to such compounds. The proposed research presented in this renewal application is said to concern the above need. Specifically, the research is to target the thermally induced ring expansions of 4-alkynyl-(alkenyl, allenyl and aryl)cyclobutenones and related imino-, thio-, and alkylidenyl- analogs to quinones, hydroquinones, phenols, heteroaromatics and a variety of cyclic aliphatic compounds. It is noted that success of these studies will provide powerful synthetic methodology with which readily available squaric acid and related cyclobutenediones function as a 4-carbon building block. The principal investigator indicates that in addition to a detailed study of the synthetic scope of these ring expansion reactions, a number of specific target syntheses of potential medicinal agents are outlined and that these include examples of natural and unnatural quinones having structural features deemed necessary for bioreductive alkylating agents and thus compounds of potential use as anticancer agents. He further notes that in addition, the design and synthesis of 4-alkynylcyclobutenones that should give unique diradicals under in vivo reductive activation are presented and that such compounds are expected to cleave DNA and thus also function as potential anticancer agents of a unique type. It is indicated that also, a general study of the use of the cyclobutenone rearrangements as key steps in developing routes to oligomers of quinones is presented and that this study is of particular potential importance since no general reliable method currently exists for the controlled synthesis of such compounds and natural dimers and trimers of quinones are now appearing that show marked antifungal and anti-HIV activity. The principal investigator states that studies that combine the cyclobutenone rearrangements with new annulation strategies are also presented and that particularly noteworthy is a new reaction in which oxonium and possibly iminium ions are generated from alkoxyquinones under very mild conditions. He notes that the synthetic utility of this reaction as a route to annulated quinones having antibiotic activity is presented.